Severe Pneumocystis carinii infections of immuno-compromised individuals, such as premature infants, children with hypogammaglobulinemia or deficiencies of cell-mediated immunity, patients receiving immunosuppressive therapy, and patients suffering acquired immunodeficiency syndrome (AIDS), leads to the development of Pneumocystis carinii pneumonia (PCP). By far the most common occurrence of PCP is in AIDS patients. More than 36,000 cases of AIDS have been reported since 1979, and 62% of these patients developed PCP ("Acquired Immunodeficiency Syndrome (AIDS) Weekly Surveillance Report", CDC (Dec. 29, 1986)). With current standard treatments, mortality for the first episode of PCP in AIDS patients is approximately 20-30%. To date, over 42,000 cases of PCP have been reported in AIDS patients (including multiple episodes), with 100,000 cases predicted to occur in the United States by 1991.
The two conventional therapies for treating PCP consist of either trimethoprim-sulfamethoxazole (TMP-SMX) administered orally or parenterally, or pentamidine isethionate administered parenterally: Hughes et al, J Pediatr (1978) 92:285-291; Sattler et al, Am J Med (1981) 70:1215-1221; Navin et al, N Engl J Med (1984) 311:1701-1702. Unfortunately, approximately 50% of patients receiving either drug treatment develop severe toxicity, requiring discontinuation of the therapy: e.g., K. A. Western et al, Ann Int Med (1970) 73:695; M. Wharton et al, Ann Int Med (1985) 105:37-44; F. M. Gordin et al, Ann Intern Med (1984) 100:495-499. Many immediate and long term side effects have been associated with the parenteral administration of pentamidine. Pain, swelling and sterile abscesses are observed at the site of intramuscular injections, and thrombophlebitis and generalized or localized urticarial eruptions are associated with intravenous administration. Severe hypotension may also develop following a single intramuscular dose, or after rapid intravenous infusion: Navin et al, supra. Hypoglycemia has also been reported in patients: Walzer et al, supra; Pearson et al, Ann Inter N Med (1985) 103:782-786. In some patients with hypoglycemia, diabetes mellitus also develops: Osei et al, Am J Med (1984) 77:41-46. Impaired renal function occurs in about 25% of patients receiving pentamidine. Other common adverse reactions include elevation of liver enzymes, hematologic disturbances with neutropenia and thrombocytopenia, fever, hypocalcemia, and hallucinations. Less common adverse effects include cardiac arrhythmias and pancreatitis. See, e.g., Pearson et al, supra.
When a patient develops an adverse reaction requiring discontinuance of one of the above standard therapies, the usual recourse is to place the patient on the alternative standard therapy. A substantial number of patients, however, develop an adverse reaction to both TMP-SMX therapy and parenteral pentamidine. Thus, the art has actively pursued alternative therapies that obviate the serious side effects associated with the above standard therapies. For example, dapsone (diaminodiphenylsulfone) has been tried both alone and in combination with TMP, to treat PCP. Dapsone has been reported to be effective in a rat PCP model: Hughes et al, Antimicrobial Aqents Chemother (1984) 26:436. Dapsone alone, however, has a failure rate for PCP of about 39%, while approximately 31% of the patients given trimethoprim-dapsone (TMP-DPS) experienced severe toxicity: G. S. Leoung et al, Ann Int Med (1986) 105:45-48; Mills et al, Int'l. Conf. on AIDS, poster 297 (Paris, France, 23-25 June 1986); Medina et al, Proceedings of the III Int'l. Conf. on AIDS, p. 208 (Washington, D.C. 1987).
Another alternative therapy is treatment with .alpha.-difluoromethylornithine (DFMO). Although DFMO was hot efficacious in a rat model of PCP, recent clinical studies report some clinical response for this drug: J. A. Golden et al, West J Med (1984) 141:613; McLees et al, Am Rev Respir Dis (1987) 135:A167. Yet another potential therapy for PCP has been suggested using the drug trimetrexate. Adverse reactions have been reported, however, and the relapse rates within one month appear to be high: Allegra et al, N Engl J Med (1987) 317:978-985.
The aerosolization of pentamidine has been studied in rodent models: R. H. Waldman et al, Am Rev Respir Dis (1973) 108:1004-1006; R. J. Debs et al, Abstracts of the 1985 ICAAC, p. 192 (Abstract No. 550); E. H. Bernard et al, Id. p. 193 (Abstract No. 552); R. J. Debs et al, Int'l. Conf. on AIDS, poster 294 (Paris, France 23-25 June 1986); E. H. Bernard et al, Id., poster 300.
AIDS patients suffering PCP are known to have higher rates of adverse reaction to certain therapies than other immunocompromised patients suffering PCP: Hughes et al, supra; Gordin et al, supra. Thus, the art is in need of a more effective therapy for PCP, particularly in AIDS patients, and none of the known or potential routes of therapy have demonstrated the ability to be both efficacious and free of adverse side effects.